In the central nervous system, the chief non-neural cells are the glial cell types. These vary in numbers and type from one part of the nervous system to another, but the two basic classes can be distinguished by their size and embryonic origin, namely the macroglia, which are relatively large cells derived from the neural plate, and the smaller microglia which stem from the mesodermal tissues surrounding the nervous system.
The macroglia comprise two cell types, the astrocytes (astroglial cells) and the oligodendrocytes (oligodendroglial cells).
Astrocytes possess small cell bodies (the nucleus is about 8 microns in diameter in man) with ramifying dendrite-like extensions. The cytoplasmic processes of astrocytes carry fine, foliate extensions which partly engulf and separate neurons and their neurites, and often end in plate-like expansions on blood vessels, ependyma and on the pial surface of the central nervous system.
The functions of astrocytes are numerous. They act mechanically as a supporting component of the nervous system. Their microfilaments, microtubules, and surface contact zones fit them for this task. They also act defensively by phagocytosing foreign material or cell debris. They can function as antigen presenting cells to macrophages and can provide a means of limited repair by forming glial scar tissue or filling the gaps left by degenerated neurons. In addition, they have essential metabolic functions in regulating the biochemical environment of neurons, providing nutrients, and regulating acid-base levels, etc.
Moreover, the astrocytes, which are able to divide in immature and mature animals, pass after mitosis through a series of structural transformations depending on their state of maturity. In areas of brain injury in young or old animals they proliferate (gliosis) to produce neural support. In a penetrating injury to the central nervous system (CNS) of adult mammals, severe tissues damage and secondary necrosis occurs in the region surrounding the wound. The degenerating effects caused by the injury are believed to generate a response in the surviving glial cells adjacent to the site of the injury (Reier et al., 1983, The Astrocytic Scar As an Impediment to Regeneration in the Central Nervous System, Spinal Cord Reconstruction, Raven Press, N.Y., pp. 163-195). The astrocyte response consists of a slight mitotic increase, an increase in size (hypertrophy), and a concomitant increase in quantity of intermediate filaments (Mathewson, et al., 1985, Brain Res. 327:61-69). Together with invading monocytes, the astrocytes act as phagocytes to clear debris within the wound cavity (Schelper, et al., 1986, J. Neuropath. and Exper. Neurol. 45:1-19). When the injury disrupts the plial lining of the brain, fibroblasts migrate into the wound cavity and multiple layers of basal lamina form over the astrocyte surface (Bernstein, et al., 1985, Brain Res. 327:135-141). The fibroblasts also produce collagen, which forms dense bundles within the surrounding extracellular spaces several weeks after injury. Thus, in adults the astrocytes, together with other cellular elements, form dense interwoven scars which fill the space vacated by the dead or dying cells in the injury area. Although the scar may help save the organism it also blocks axonal regeneration and the individual is left with an irreversible functional deficit or epileptic focus depending on the site of the lesion.
Previous studies by the inventors and others indicated that penetrating lesions in the central nervous system (CNS) of neonatal mammals rarely resulted in the formation of glial scars similar to those observed in adults and that the production of typical adult glial scars after injury increased after the first two postnatal weeks in rodents (Barrett, et al., 1948, Exp. Neurol. 84:374-385; Smith, et al., 1986, J. Comp. Neurol. 251:23-43).
Previous studies on regeneration have demonstrated that CNS axons have the potential to grow long distances through peripheral nerve grafts (Friedman, et al., 1985, J. Neurosci. 5:1616-1625) or Schwann cell bridges (Kromer, et al., 1985, Proc. Natl. Acad. Sci. U.S.A. 82:6330-6334). However, the studies with peripheral nerve elements indicated that regenerating nerve fibers could only extend a short distance upon reentry into the CNS, most likely due to the formation of scars at the ends of the graft. In addition, after repeatedly crushing or cutting the dorsal roots near their entrance point in the spinal cord, the peripheral sensory fibers are regenerated only as far as the dorsal root entry zone (DREZ) of the spinal cord but no further. The problem at the DREZ is analogous to the failure of axon regeneration throughout the remainder of the CNS. Although the distance needed to reconnect the regenerating sensory fibers with their denervated dendrites in the dorsal horn of the spinal cord is relatively short (i.e., only fractions of a millimeter in the adult rat), this scant distance is normally never breached by regenerating sensory fibers in adult animals. Thus, although the injured adult CNS is potentially capable of a considerable amount of regeneration, sprouting is usually abortive and the axons fail to reinnervate their appropriate targets.
In addition, studies by the inventors indicated that developing axons are guided by oriented "highways of astroglial tissues" (Silver, et al., 1979, Dev. Biol. 68:175-190; Silver, et al., 1982, J. Comp. Neurol., 210:10-29).
The inventors have shown that in early postnatal lesion-induced acallosal animals, an untreated, properly shaped nitrocellulose (Millipore) filter, placed adjacent to the neuromas and spanning the lesioned cerebral midline, can support the migration of immature glia (Silver, et al., 1983, Science, 220:1067-1069).